Marc E. Agronin, MD

To wrap up my final question, how will the future of our field look with increasing early diagnosis of Alzheimer's? Now that we have targeted therapies to you know change trajectory, potentially disease-modifying. Yes, no – Again, we can fight about the data. We're not going to talk about the data today, we've talked about that a lot in other things, and other sessions, and there's lots of data out there. How do you think our field is truly going to change with an emphasis on early diagnosis? Is this feasible? You and I have had more calls in the last 3 days. Speaking myself, in the last 3 days, I've had more calls and emails than I've had in the last, I would say, almost a year? I don't know. Six months easily combined in literally the first 3 days since approval. How is this going to change? Are we going to be screening people more like really this time? Are we going to be bringing people earlier? Are people going to understand what MCI [mild cognitive impairment] is? Our primary care doctor is going to be able to make these types of very challenging decisions. I have a waitlist. I'm not sure if you have a waitlist. I bet you do. What's the future going to be like? What are the next 3, 6, 9, 12 months and 2 years going to look like? 

Well, my hope and this is longer than 3, 6, 9 months since I'm thinking 10, 15 years from now. I would use the model of colonoscopies. I think everyone in their 50s is going to have a multi-level screening. It's going to involve blood tests for amyloid and tau, to begin with. It will involve probably computerized cognitive testing, similar to a lot of what you do in your prevention clinic because you're trying to detect early. You'll have a battery of tests, a little more complicated than a colonoscopy, but maybe a little simpler in other respects. 

That's going to give you an increasing risk, an indication whether this is really Alzheimer's and we will do that to the end of getting you on preventative treatment, and not just lifestyle issues which you've done a lot of work in which is really critically important. Everyone should be focusing on healthy lifestyle, but some sort of specific whether it's immunotherapy or some of these other emerging treatments that you will begin before you become symptomatic. Maybe not 10 or 15 years, it may be a little longer than that, but I envision that's what's going to be the future to actually eradicate this disorder, because you're going to have to start in your 50s. If you wait longer than that, it's going to be a little too late. It’s my guess. Now, that will be for Alzheimer's disease, we have to remember that we still have other forms of neurocognitive disorders like Lewy body disease which are in many ways’ tougher diseases. We have to make sure we keep our focus on those as well, because those are equally as devastating to people and their loved ones. 

 I had a patient today came to me for a prevention, or risk reduction, or learning more about what he could do for modifiable Alzheimer's, and I got the pathology report of his father and he had Lewy body. I said, "Oh, well did he have funny dreams? Oh, yes, he acted out his dreams. He would kick and punch in his sleep. Oh, yes, we'd see these little animals and things like that. That was just Alzheimer's, right?” No, that was Lewy body. Lewy body prevention and treatment are the next frontier and subdividing. Now, that we're going to have these biomarkers is there to, so I completely agree. 

Well, Dr Marc Agronin, this has been a long time coming. We're talking about a new FDA-approved drug. For all the good, for all the bad, for all the controversy, it's here. As physicians that care about our patients and want to help them, we have to figure out some way to help them to balance the risks the benefits, and of course, the costs which we talked a little bit about today. I think our jobs just got a lot harder. 

 As long as it leads to better patient outcomes, it's great but I guess that we'll have to figure that out as things come in and who at what stage, at what dose. We'll hopefully know a lot more, hopefully, we can continue the conversation, and have a similar conversation again. 

 It's true. It's just as you said, it's here, whether clinicians agree, disagree are skeptical, hopeful, it makes no difference. It's here, and we all have the obligation to get on board and get involved with our patients and do what's going to be in their best interest. It's going to be a work in progress but we can't shy away from that. 

 They're going to come to us with questions and that's why you have to give our best opinion. Thanks so much for watching this 

. If you enjoy this content, please subscribe to our e-newsletters to receive upcoming programs and other great content in your inbox. Dr Agronin, thanks so much. 

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Drs Richard S. Isaacson and Marc E. Agronin look to the future of treating Alzheimer disease with the emphasis on early diagnosis. 

Future of Treating Alzheimer Disease 

I just wanted to wrap up on a couple of things. First, blood-based biomarkers. Where's our field going? I think and I hope that our field is going towards blood-based biomarkers, PET [positron emission tomography] scans, expensive and cumbersome radiation. Then we have spinal taps. I like spinal taps to get amyloid and tau. It's reliable. I've been used to it. Patients don't want spinal taps, it's cumbersome, takes a lot of time. Serum biomarkers, the first commercially available amyloid blood biomarker test is available now, I think in most states but not every state. Tau test, P-tau217, for example, are really interesting and compelling data as a biomarker. Whether or not these are used for 1-time diagnostic slices to predict or correlate with positivity of an amyloid or tau scan and that is used for it helping with diagnosis or stratifying with who should get a PET scan or whatever else, or whether it's used to maybe track people over time and wouldn't it be great to have it just like we do HDL [high-density lipoproteins] cholesterol, and LDL [low-density lipoproteins], and total cholesterol in a year and a half, 2 years we’re going to be every 6 months getting amyloid and tau. Also, maybe monitoring trajectory that way? “Oh, they have amyloid but no tau. Oh, maybe they're really early, maybe we need to intervene with the anti-amyloid drug.”

These are all hypothetical things. They sound good, they sound exciting, I'd love to track my patient’s amyloid every 6 months over time, and I want to do that and maybe even plan on doing it, but how realistic is this? When are serum biomarkers, even though they're available, they're going to be available more, how much do we know, and don't know, and what can we expect about serum biomarkers? 

There's a lot of work that needs to be done here. We need to be very cautious that we're not basing diagnoses on these results. There's no question within the next 5 years that we will have relatively accurate ways through just a blood test to detect the presence of amyloid and tau. The question again, is what does that really mean? Does that mean they have Alzheimer's disease? What about someone who has tau but not amyloid or vice versa? Or what about as we're seeing clinical trials where you have a positive tau blood test and you have a negative tau scan? We know this is a heterogeneous disorder, there's different subtypes, depending on where you have deposition in the brain is going to determine to some extent the course for some individuals. 

You can have Alzheimer's disease, at the same time if you have Lewy bodies in the brain. The complexity here is great, and the more you reduce it to single tests, to some extent, you really risk going down the wrong course. I give this example, no one will go to a doctor on a single blood test want them to say, "Yes, you have this cancer or no, you don't". There are other clinical correlates that you have to mix in with this. As the severity of the diagnosis is a life-changing diagnosis, these tests are not like getting to check your cholesterol level or indicating you're a little anemic or not. This is a life-changing diagnosis, and so we owe our patients, their families and loved ones, and we ourselves as clinicians to be careful, cautious, and to be comprehensive. That's the strength of memory disorder centers of the center you have where we put the whole puzzle together. We're not looking at 1 single data point but everything in aggregate and trying to assign something. I would hope that this is going to continue to be the approach and that requires a lot of education and specialists as well. 

I'm really glad you said that. I just want to repeat that for a second, because I get excited about things. I like thinking about the future. I like figuring, “OK, where are we going to be in 5 or 10 years?’ I'm going to try to do that now or yesterday, right? I can't wait till the amyloid blood test come out, but I just want to reiterate what you said. Currently, in medicine, we've come pretty far in certain areas and we would never make a diagnosis of cancer, almost never basically on 1 test, right?

We confirm it, we get corollary, we do that, we repeat it we, so I completely agree. I'm excited about the promise of blood-based biomarkers but we have to be careful. It has to be in the right clinical picture, progressive short-term memory loss, family history of Alzheimer's, to e4 variants. Then the amyloid test in the blood is sky-high. It's probably Alzheimer's disease but I completely agree with you. The panel of tests, the other additional markers, and confirmatory tests, especially if someone's going to be going in a clinical trial, I think it's really important.

The use of blood-based biomarkers for diagnosis of Alzheimer disease in the context of the comprehensive diagnosis. 

Blood-Based Biomarkers for Diagnosis of Alzheimer Disease 

We've talked a lot about aducanumab. What does this do for the rest of the field? How does this impact the treatment landscape of Alzheimer's disease and what about all these other drugs in development? We talked about lecanemab, which is being studied for both early Alzheimer's disease, dementia, mild cognitive, and impairment being studied in large phase 3 studies. We have a galantamine, for example, that's a recent made a big splash a few months ago. Donanemab showed some interesting results too. Fast forwarding, after that 

] paper, there is going to be phase 3 study launching all over now. Here we go again, another antibody has potential, it failed in 1 way but maybe positive in other patients and other subgroups? How do you think this approval affects those studies which you mentioned before where people may not want to enroll? Do you think that increases the likelihood of success that the FDA will look at these data and say, "We don't need a cognitive measure because, on label, there's no cognitive anything in the label for aducanumab. It's a biomarker-based disease". Do you think these additional anti-amyloid agents are going to have a higher likelihood of success based on the precedent that the FDA has now seen? 

Yes, and I would throw into the mix anti-tau treatments also that are being looked at. Yes, so this is 1 question that's been raised is, given the FDA's approach here, is this going to set a precedent for the change the bar in terms of other treatments? I've been to some FDA review committees and it's a tough environment for any treatment for Alzheimer's disease. Almost everything has failed through it and with good reason, either the data is there or it's not there. We need data and we need studies. If someone is presented with a 2-year on average, placebo-controlled trial of some other immunotherapy or any other Alzheimer's treatment. I would add to that that the screening process is very rigorous. I have some studies where it's a 2 or 3-month process of multiple scans, multiple scales, and someone is asking themselves, "Am I going to go through that process for 2 years that to be on potential placebo? I can walk down the street and get this infusion.”

It's going to be an issue and so one question I raise is do we need to change the scope of some clinical trials? Do they need to be shorter? Do they need to get into more quickly open-label? Do we need to make aducanumab a comparator? I don't have answers to these questions, but there's no question as a researcher, and I'm certain any company working on clinical trials, any researcher trying to generate a clinical trial is going to have to think about this in terms of what they're competing with. I'm concerned about its impact on research. I know a lot of people are. Again, it's an issue that is yet to be determined. My sense is, I'm trying to be very optimistic here, is that I think this is going to be a very gradual rollout. I think what we're going to see both from clinicians and payers, is that there's going to be a pretty high bar to qualify for the treatment to get payment for it. Sure, some people are going to walk in and just want to pay cash for this. I don't think that's going to be the majority. I think that will be few and far between, so I think it's going to be done in a very measured way. At least, I hope it is, and this is part of the reason we're talking about this because I think you know these questions really have to be vetted and discussed on every level. There is some consensus because we've seen some of the controversy, we've seen some of the concerns raised amongst colleagues. I think in general, it's better when people are on the same page when we agree on what the best approach is. We want consensus at the end of the day.  

Yep, I agree, and I completely agree with all of your points. Patients do what they want to do and it even opens up the door to what if someone is on aducanumab, they're in another clinical trial and it could be mixing so there's lots of potential issues there that we need to have very frank conversations with patients about. I think that happening is going to be very few and far between, at least I hope it would be. However, there's actually studies being planned for that now. Obviously, if you're on an anti-amyloid drug in a clinical trial, you really should not be on the anti-amyloid drug in practice, that’s easy. But what about an anti-tau drug in clinical trial, but being on the amyloid drug in front? That probably mixes things up and confuses things, but, for example, there's a phase 3 study. It's going to enroll over 3,700 people with semaglutide.

Semaglutide is a GLP-1 drug. It's basically a diabetes drug that's been studied and has some interesting outcomes with cognition and Alzheimer's disease. Basically, they're going to be evaluating whether semaglutide for a 2-year trial, can slow Alzheimer's progression, and actually improve cognitive function. That study to my understanding, I think I probably need to double-check this, but it allows someone to be an anti-amyloid drug. There may be some studies that people could go into and participate in as well as being on aducanumab. How do you track that? How do you analyze for that? Obviously, it's a randomized trial so hopefully, some of that will shake out but it really adds just a whole another level of I guess statistical complexity, real-world complexity, recruitment complexity, when you have a drug like this available in the market. 

 We have people on acetylcholinesterase inhibitors and memantine who are in trials that we know has a potential to affect to confound the data to some extent. You're right, it may be that it becomes an acceptable treatment. I'm seeing over time; I would say across the board for not just Alzheimer's studies but other clinical trials, are a greater and greater allowance for other modalities being used simultaneously. Obviously, someone can't be on more than 1 clinical trial at the same time but I think realistically, your point is probably going to become more the reality that either the studies allow these other treatments or they're really going to have a hard time enrolling. 

You also point out how important it is in addition to immunotherapy to look at these other modalities and other ways to try to get at this disease. As much as we know that the data, that the FDA based approval on and this aducanumab. What we're imagining we'll see with other immunotherapies is that it can rid the brain of amyloid, that there's the potential to slow to the disease course down. We clearly need more than that, we need better than that, and we don't want to compromise studies that are looking at other modalities and other ways to get at this disease. That's critically important.

Impact of the approval of aducanumab on the treatment landscape and other drugs in development for the treatment of Alzheimer disease. 

Impact of the Approval of Aducanumab on the Treatment Landscape in Alzheimer Disease 

I have a very unique practice, as you know. In the Alzheimer's prevention clinic, we only see people in the pre-dementia phase, so we see preclinical Alzheimer's patients that we've identified as having amyloid, but no symptoms or minimal symptoms that are not even close to MCI [mild cognitive impairment]. We see people with MCI, no dementia. They can still go about their activities of daily living. We already have this very robustly well-characterized group of people, very unique, though not very common. The question that I have is how do you identify the appropriate patient? How do you in clinical practice figure out who should go on aducanumab because the label is so broad? The treatment of Alzheimer's disease to me, if I'm looking at the definition of Alzheimer's, I include stages 1, 2, and 3, but the research data only really looked at people with MCI and early Alzheimer's disease in terms of their mini-mental, or in terms of their functioning.

The other part about how I look at who is the appropriate patient, it's not just about the efficacy part and which patient group should this drug be used to promote efficacy, which is, I guess, cognitive maintenance, or cognitive improvements, or reduction of amyloid? What is the definition of efficacy? That's complicated. Who is the appropriate patient from a safety perspective? In the Alzheimer's prevention clinic, we're already doing cognitive tests every 6 months. Well, that's helpful because we can understand trajectory. In the Alzheimer's prevention clinic, we're doing APOE [Apolipoprotein E] on everybody because the APOE4 variant increases risk a little bit, not good for diagnosis necessarily, but we use it to help personalize care, it is complex, a little controversial, but we use the APOE4 variant and it's helpful for us. I know that when a person with the APOE4 variant, actually, when they have 2 of them, they may be at higher risk for ARIA [amyloid-related imaging abnormalities], for vasogenic edema, for bleeding. They need to be more cautious with the dosing. Maybe we need to have a different titration schedule? We have a label that says treatment of Alzheimer's disease. We have a label that says do an MRI [magnetic resonance imaging] at 7 months and 12 months. Well, what if a person has 2-week 4s versus E33? We have a label that is so broad. I guess this is again, a lot to talk about, but what is the appropriate patient from an efficacy and a safety perspective based on the data and based on your feelings?  

 Well, to start with the efficacy front, the work you've done has really been pioneering in terms of looking at prevention. We know we need to start early and identify those individuals. Ideally, those are the individuals who we treat with this, because going back to my analogy before about the fire in the house, you want to put it out before there's a lot of damage. The brain does not repair itself as readily and as quickly as other parts of your body, we just know that. Theoretically, the earlier we catch in a rid the brain of amyloid and tau, we would imagine, now this is not based on the data we have yet, but we would imagine and want to get immersion data showing that that will actually push off the emergence of this disease. It will really slow it down, but yet, we still have to establish that. On the 1 hand, those theoretically are the ideal patients. We need more data to really support that. Years before they get symptoms, that's when we should be using this, but we haven't really identified them or diagnosed them formally as Alzheimer's disease. You've identified the key challenge. Most of the calls I'm getting are from individuals or loved ones of individuals who have moderate to severe disease because they're willing to do anything, even if this is a Hail Mary and somehow would slow it down, and yet we know that they will not be appropriate because there is no data showing it's going to have an impact at that point. The efficacy thing I think will be straightened out over time. I think it will be a combination of clinicians and working with the payers and the insurance carriers to determine what's even to be covered in the first place. I am concerned about access to diverse communities because I think that there's going to be a greater challenge there. The other thing is that centers like you, centers like me, we're not-for-profit site. In terms of being able to give these treatments, sometimes it's more challenging and there's more barriers. 

The infusion sites in the community that we have to partner with, there's just a lot to be worked out. Safety is also important. On the 1 hand, I can tell you from being an investigator for every major immunotherapy trial over time, that we definitely see ARIA, whether it's vasogenic edema, or whether it's these microhemorrhages. However, most of the time it's asymptomatic. When it's symptomatic, it tends to be pretty mild. That's the good news about this. I think some of the accounts I've been reading tend to describe it a little more severe than it typically is, but usually, if we catch it, it's usually earlier than 7 months in some individuals. I have a question about waiting that long, and what if someone doesn't want to get an MRI, or what if someone can't get an MRI for some reason? What about individuals who because of a pacemaker or some metal in their body, they have early Alzheimer's disease, but you can't do an MRI? They're now ineligible for this, what do you do? Those safety issues also need to be clarified. I think what you're pointing out very clearly here is that in this first week amidst a lot of the hoopla and a lot of hope, there's so many questions and so many issues and concerns being raised that we really have to take our time to address these before rushing into wholesale treatment of individuals with this new agent.  

 I agree. In night 1, first night from 7:45 p.m. to at least 10 p.m., I was getting back to patients. I treat a lot of MCI patients. I have a lot of pre-clinical Alzheimer's patients. The patients I was calling back on that Monday night, every single 1, was invariably moderate to severe disease. Those are the patients that were calling, those patients that were emailing. “What can we do? I will rent an apartment in New York because we can't travel back and forth. If this is going to be it, we'll get a studio. We'll do whatever it takes.” You're exactly right. The people that are most interested at this exact moment, in those days, the sooner week, days, and weeks soon after, will be people that haven't really been shown to be effective that where the drug hasn't been tested and shown to be effective.  

 The other side of the concern of mine because there are people who, for good reason are desperate. It's been almost 20 years since any approved treatment and they're willing to pay money and do what they need to do. You and I both see that they do things sometimes that have no scientific validity and they're exploited at times and they end up spending a lot of money on treatments that there's no evidence for. I'm concerned, in this case, if there will be areas in which people are just going to pay just to get it done even in those stages where it's not supported.  

 The other side of the coin which I think will defer for conversation at this time, maybe we can talk about this offline but pre-clinical Alzheimer's disease never been studied. We don't really have data. We have the A4 study using solanezumab in a preclinical Alzheimer's population. We have other studies the AHEAD 3-45 study which is going to be using lecanemab or BAN2401. It was the old name. Looking at more of the preclinical population, actually, they even defined it as early preclinical and I think later pre-clinical, something like that. Is this going to be used for people with pre-clinical Alzheimer's disease? When do you pull the trigger? That's off-label, or is it off-label? Because, it says the treatment of Alzheimer's and pre-clinical Alzheimer's diseases invariably Alzheimer's disease, or is it?  

That's a key point. What's on-label and what's off-label because we know how the diagnosis. It varied over time and we make clinical diagnoses without biomarkers all the time so does that count? There are no biomarker specifications.  

It's going to be an interesting several weeks and an interesting several months, I think for sure. 

The challenges of identifying the appropriate patient, earlier in the disease course, for treatment with aducanumab for Alzheimer disease.  

Marc E. Agronin, MD

Articles

Future of Treating Alzheimer Disease

Blood-Based Biomarkers for Diagnosis of Alzheimer Disease

Impact of the Approval of Aducanumab on the Treatment Landscape in Alzheimer Disease

Identifying the Appropriate Patient for Treatment with Aducanumab in Alzheimer Disease